Effect of electrical cardioversion on 1‐year outcomes in patients with early recurrence after catheter ablation for atrial fibrillation

Abstract Background Atrial fibrillation (AF) recurrence is common in the 3‐month blanking‐period after catheter ablation, during which electrical cardioversion (ECV) is usually performed to restore sinus rhythm. Whether ECV can affect the clinical outcome of post‐ablation AF patients is inconsistent, however. We aimed to explore the 1‐year effect of ECV on AF recurrence and rehospitalization in patients experienced recurrence within 3‐month after AF catheter ablation. Methods Patients who experienced recurrence within 3‐month after AF catheter ablation procedure were enrolled from the China Atrial Fibrillation Registry (China‐AF). A 1:3 Propensity score matching (PSM) method was applying to adjust the confounders between patients who had been treated by ECV or not. Logistic regression models were conducted to evaluate the association of ECV with 1‐year AF recurrence and rehospitalization. Results In this study, 2961 patients experienced AF recurrence within 3‐month after the procedure, and 282 of them underwent successful ECV, 2155 patients did not undergo ECV. One‐year AF recurrence rates were 56.4% in ECV group versus 65.4% in non‐ECV group (p = .003), and were 55.9% versus 65.9%, respectively, after PSM (adjusted odds ratio [OR] 0.66; 95% confidence interval (CI): 0.49–0.88, p = .005). However, the difference of 1‐year rehospitalization rates between two groups were not statistically significant before (ECV group: 23.7% vs. non‐ECV group: 22.3%, p = .595) and after PSM (ECV group: 24.4% vs. non‐ECV group: 21.6%, adjusted OR1.14; 95% CI 0.81–1.62, p = .451). Conclusions Successful ECV was associated with lower rate of one‐year recurrence in patients with early recurrent AF after catheter ablation.


| INTRODUCTION (BACKGROUND)
Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. Its incidence increases dramatically with age and underlying heart disease. It is recognized as a global public health problem due to its significant burden of morbidity and mortality. [1][2][3][4] Catheter ablation of AF is effective in restoring and maintaining sinus rhythm. Nowadays, it is gradually being widely used to treat AF improving the overall symptom burden and quality of life. [5][6][7][8] Although its efficacy has been established, arrhythmia recurrences thereafter still remain an important issue. AF recurrence rates have been reported in up to 50% of patients in the early 3-month after catheter ablation. 5,8 The current expert consensus statement recommends that early recurrence of atrial arrhythmias in a 3-month "blanking period" should not be considered as ablation failure, and repeat ablation should not be performed routinely, except in special cases. 5 Pharmacological cardioversion and electrical cardioversion (ECV) are commonly used in patients with early recurrent AF following ablation procedure. 7,8 However, the effects of antiarrhythmic drugs are unpredictable, with high rate of adverse effects. 9 ECV is an efficient and safe procedure to restore sinus rhythm, with high-initial success rate, but the long-term maintenance of sinus rhythm remains a challenge. [10][11][12] Whether restoration of sinus rhythm by ECV in patient with early recurrent AF after catheter ablation is associated with improved clinical outcomes remains unclear. Our study aimed to evaluate the association between successful ECV and clinical outcomes in AF patients with early recurrence after catheter ablation using data from the China Atrial Fibrillation Registry (China-AF) study.

| Study population
We used data from the China-AF study. It is a prospective, multicenter, hospital-based, on-going registry of patient with AF from 31  BMI was calculated by dividing weight in kilograms by the square of height in meters. Current smoking was defined as regular smoking within 1 month and at least one cigarette per day, and current drinking was defined as regular drinking within 1 month and at least 50 g of alcohol each time. Established CAD was defined as having any history of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting. AADs included class I (propafenone, moricizine, mexiletine) and class III (amiodarone, sotalol). Rate-control drugs included β-blocker, non dihydropyridine calcium antagonists and digoxin. CHA 2 DS 2 -VASc was calculated by assigning 2 points for a history of stroke/TIA/TE and age ≥ 75 years, 1 point for age between 65 and 74 years, a history of hypertension, DM, congestive heart failure, vascular disease, and female sex.
Patients were followed-up at 3 months, 6 months, and every 6 months thereafter by trained staff, at the outpatient clinics or through telephone interview. Information relating to medical therapies, Holter electrocardiography, repeat ECV, repeat catheter ablation, surgical ablation, pharmacologic cardioversion and rehospitalization were collected at each follow-up occasion.

| Study outcomes
The primary and secondary clinical outcome was one-year incidence of AF recurrence and rehospitalization after catheter ablation, respectively.
In this study, AF recurrence was defined based on the symptoms
Compared to non-ECV group, the OR of AF recurrence in ECV group was 0.66 (95% CI 0.49-0.89, p = .004) in univariate logistic regression analysis. In multivariate logistic regression analysis, it was 0.66 (95%CI 0.49-0.88, p = .005). We found that the ORs of ECV and AF recurrence were homogenous within different subgroups ( Figure 3). F I G U R E 1 Flowchart of patients. AF, atrial fibrillation; ECG, electrocardiogram; ECV, electrical cardioversion F I G U R E 2 AF recurrence rates in patients during follow-up before and after PSM. AF, atrial fibrillation; ECV, electrical cardioversion; PSM, propensity score matching F I G U R E 3 Subgroup analysis for AF recurrence rates in patients with and without ECV. Models were adjusted for antiarrhythmic drugs and rate-control drugs during the follow-up. AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; CHF, chronic heart failure; ECV, electrical cardioversion; LAD, left atrial diameter After PSM, they were 18.7% in ECV group and 15.9% in Non-ECV group (χ2 = 1.02, p = .312) (Figure 4(B)). Compared to non-ECV group, the OR of AF rehospitalization in ECV group was 1.22 (95%CI 0.83-1.79, p = .312) in univariate logistic regression analysis, and 1.22 (95%CI 0.83-1.80, p = .310) in multivariate logistic regression. The ORs of ECV and cardiovascular rehospitalization were homogenous within subgroups ( Figure 5(B)).

| DISCUSSION
In this large contemporary cohort of Chinese patients with nonvalvular AF, we found that ECV was associated with lower recurrence rate during one-year follow-up in patients with early recurrent AF after catheter ablation. We observed no relationship between ECV and rehospitalization or cardiovascular rehospitalization at 1 year, also in the subgroup analysis.
Previous studies 5,14 reported that early recurrence rates of AF after catheter ablation variated between 16% and 65%, and might be related to transient inflammatory reaction resulting from ablation lesions or pericarditis. Other possible mechanisms include a transient imbalance of the autonomic nervous system, which being an arrhythmia trigger, and a reconnection of PVs. [15][16][17] AF causes electrical and structural changes driving the atrial remodeling process. 3,18,19 The proinflammatory phase following ablation also F I G U R E 4 AF rehospitalization rates (A) and cardiovascular rehospitalization rates (B) in patients during follow-up before and after PSM. AF rehospitalization rates (A) in patients during follow-up before and after PSM. Cardiovascular rehospitalization rates (B) in patients during followup before and after PSM. AF, atrial fibrillation; ECV, electrical cardioversion; PSM, propensity score matching favors to the maintenance of AF. 20 When AF persists, the progression of AF is facilitated to result in fibrosis and enlargement of left atrium. The reduction of AF burden could initiate a long-term process of reverse remodeling. 3,21 Some studies supporting rapid functional and structural remodeling during AF encourage the clinician to administer cardioversion early in patients with recurrence after AF ablation. 3,5 So, we believe that maintenance of sinus rhythm during the "blanking period" after ablation is beneficial to improve long-term outcomes. 18 In clinical practice, we usually administer AADs, ECV to restore sinus rhythm in these patients. Patients who experience early recurrence of AF are more likely to have persistent AF in the long run, 14,22-24 approximately 30%-50% of patients with an early recurrence may later remain free from recurrent atrial arrhythmias. 18,23,25,26 Therefore, early repeat ablation is not recommended routinely in patients with early recurrence after ablation. 5 Additionally, despite the use of AADs, it may suppress nonspecific arrhythmias and reduce hospitalization in the immediate post-ablation period, but it does not affect the underlying disease course in the long term. 14,22,27,28 Early ECV after AF catheter ablation appears effective to maintain sinus rhythm, minimize late AF recurrence, reduce chronic AADs use, and avoid re-ablation procedures.
F I G U R E 5 Subgroup analysis for AF rehospitalization rates (A) in patients with and without ECV. Models were adjusted for antiarrhythmic drugs, rate-control drugs and anticoagulant drugs during follow-up. AF, atrial fibrillation; CAD, coronary artery disease; ECV, electrical cardioversion Previous studies have failed to reach a consistent conclusion as to whether ECV usage in patients with early AF recurrence after ablation was associated with the reduction of AF recurrence. The reason for this inconsistency is unclear but may be related to study population, definition of AF recurrence, follow-up protocol and statistical methods. Contrary to our findings, in a study conducted by Johns Hopkins Hospital, Chilukuri et al. 29 reported the outcomes of patients who underwent cardioversion for persistent AF/AL following ablation.
They showed that not only >80% of patients who underwent cardioversion for persistent AF/AL after AF ablation had recurrence, but also early or late ECV (within 90 days or between 90 and 180 days following ablation) did not affect the outcome. Ebert et al. 22 also failed to reveal that successful early ECV after AF ablation could prevent more recurrence of AF. However, consistent with the findings of our study, in a prospective study, 18 Malasana et al. demonstrated that patients undergoing their first cardioversion early after ablation (<3 months) were more likely to remain free from arrhythmia at 1 year.
An aggressive strategy of rapid cardioversion post-ablation reduces the significance of recurrent AF/AL and prevent the long-term need for recurrent ablations or chronic antiarrhythmic medications during the first 6 months. In another retrospective study, 30 Baman et al.
founded that freedom from AF/AL was achieved in approximately 50% of patients who undergo cardioversion within 30 days of a persistent atrial arrhythmia after catheter ablation of AF. Patients who underwent early cardioversion within 30 days of arrhythmia recurrence were >20 times more likely to remain in sinus rhythm than patients who were cardioverted after 30 days, regardless of the timing of recurrence or whether concomitant antiarrhythmic drug therapy was used. Our observation suggested that the usage of ECV to restore sinus rhythm may be associated with the reduction of AF recurrence in the long term for those patients. Early restoration of sinus rhythm after AF recurrence may facilitate the long-term maintenance of sinus rhythm. Nevertheless, our study patients came from the largest, prospective, multi-center registered AF study in China, including paroxysmal and Non-paroxysmal AF. Moreover, AF recurrence in our study include AF, AL, and AT.
Symptom status may be a marker of high risk for hospitalization.
Similar to the result of Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) study, 31 they revealed patients with more severe symptoms and requiring electrophysiology management were also more likely to experience hospitalization. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study 32 pointed out that cardioversion was a maker of lower quality of life and greater symptom burden. They found that hospitalization rates were higher in patients with a rhythm control strategy relative to rate control (80% vs. 73%, p < .001). Pokorney et al. 33 also demonstrated that patients that received cardioversion were at high risk of rehospitalization and symptomatic progression of AF. The reason may be when patients with symptomatic AF recur after cardioversion, they may be more aware of the impact of AF on their quality of life.
Patients without cardioversion had adapted to the limitations of their symptoms over time. In our study, the usage of ECV in patients with early recurrence after AF ablation could not be associated with lower rates of rehospitalization and cardiovascular rehospitalization. Moreover, in the subgroup analysis, rehospitalization appeared to be higher in patients with paroxysmal AF. Patients requiring ECV usually have more severe symptoms, exertional limitation, and poor tolerance.
Patients with paroxysmal AF also have more obvious symptom. These reasons lead to more rehospitalization and require more aggressive rhythm control. Contrary to our findings, Tripathi et al. 2 reported ECV during index admission was associated with a significant reduction in 30-day readmissions and service charges. This may be partly due to the heterogeneity of the study samples (our study samples were patients with early recurrent AF after catheter ablation), partly due to the period of study time (the duration of our study was 1-year).
Among the patients included in our study, most of them were younger male with insurance, so they were more likely to be actively hospitalized for rhythm control therapy. In agreement with our study, Patel et al. 34 showed marked increases in AF hospitalization among those ages 35-64 years, possibly due to more aggressive inpatient treatments such as AF ablation, direct current cardioversion in this younger population. Although patients are hospitalized more frequently and treated with more costly and aggressive inpatient therapies, but this is associated with improved outcomes including decreased rates of in-hospital mortality and long-term mortality. 4

| STRENGTHS AND LIMITATIONS
The China-AF registry is the largest prospective cohort in China and these data were from clinical practice, our results were certainly applicable and instructive. However, this was an observational study and should be considered hypothesis generating.
Despite an aggressive PSM technique, residual unmeasured confounders may influence the findings. Patients with asymptomatic AF or other under-reporting situations, such as insufficient continuous ambulatory rhythm or ECG monitoring might affect results of our study. Although the China-AF study population was large, the proportion of patients with ECV was relatively low, which may have an effect on the outcome. Lastly, the follow-up time period of 1-year was relatively short.

| CONCLUSIONS
Our study showed that successful ECV was associated with a lower rate of 1-year recurrence in patients with early recurrent AF after catheter ablation, but not associated with the rates of rehospitalization and that for cardiovascular rehospitalization. The sponsor of the study had no role in study design, data collection, data analyses, data interpretation, or writing of the report.